Smyth M J, Kelly J M, Baxter A G, Körner H, Sedgwick J D
Cellular Cytotoxicity Laboratory, The Austin Research Institute, Heidelberg, Victoria 3084, Australia.
J Exp Med. 1998 Nov 2;188(9):1611-9. doi: 10.1084/jem.188.9.1611.
Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I- variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I- RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3(-) NK1.1(+) cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I- prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte-mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I- tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.
自然杀伤（NK）细胞被认为是抵御肿瘤的第一道防线，尤其是针对主要组织相容性复合体（MHC）I类变体肿瘤。我们在缺乏穿孔素的C57BL/6（B6）小鼠中证实，未致敏小鼠腹膜内MHC I类RMA - S肿瘤细胞的生长受CD3（ - ）NK1.1（ + ）细胞介导的穿孔素依赖性细胞毒性控制。此外，我们证明缺乏肿瘤坏死因子（TNF）的B6小鼠在排斥RMA - S方面也存在显著缺陷，尽管RMA - S在体外对TNF不敏感，且来自B6和TNF缺陷小鼠的脾脏NK细胞对RMA - S的杀伤作用相同。与B6或穿孔素缺陷小鼠相比，在用RMA - S或RM - 1（一种B6 MHC I类前列腺癌）攻击的TNF缺陷小鼠中，NK细胞向腹膜的募集被消除。TNF缺陷小鼠腹膜内NK细胞迁移减少与这些小鼠中NK细胞对肿瘤的反应缺陷相关。相比之下，缺乏TNF并不影响肽特异性细胞毒性T淋巴细胞介导的对预免疫小鼠腹膜内肿瘤的排斥。总体而言，这些数据表明，递送穿孔素的NK细胞是腹膜内I类肿瘤排斥的主要效应细胞，且TNF对其募集到腹膜特别关键。
